Ocular herpes infections are one of the major infections in the United States. Effective antivirals are available to treat the acute infections, but there is no drug or vaccine available to prevent the recurrences and avoid the cumulative effects and the morbidity produced by these recurrences. We have developed new animal models for studying recurrences of ocular herpes infections and viral reactivation which do not rely on trauma for producing the recurrences, and we will use these models to study the host factors involved in viral recurrences, and mechanisms of blocking the recurrences. The specific aims of this study are: A] to test the hypothesis that stress-related recurrences of herpes are adrenergically mediated and that blocking the mediator reduces recurrences, and B] to prevent HSV recurrences by inhibition of latent virus multiplication. The non-specific beta-adrenergic receptor blocker propranolol reduces viral reactivation in mice subjected to heat stress, and reduces the incidence of recurrent keratitis in rabbits. Other non-specific beta- blockers, specific beta1 and beta2 blockers, and alpha adrenergic receptor blockers will be tested in the animal models to determine which cell surface receptors are involved, and which blockers might be efficacious when tested in humans. Beta-blocked are currently used in humans to treat a variety of conditions, and are relatively non-toxic. Herpesvirus requires various unique enzymes for its multiplication such as thymidine kinase. The trigeminal ganglion and the central nervous system are deficient in thymidine kinase, and we have hypothesized that it should be possible to block viral recurrences from the ganglia (the major site of latent herpes) by treating with specific viral thymidine kinase inhibitors while having little or no effect on peripheral cells. We propose to test new viral thymidine kinase inhibitors that have promising pharmacokinetic properties. In addition, ribonucleotide reductase inhibitors and inhibitors of DNA glycosylase will be tested to prevent recurrences. An effective drug that would reduce ocular herpetic recurrences could prevent the severe corneal damage and morbidity caused by repeated episodes of disease.